The present invention, in some embodiments thereof, relates to novel therapeutic agents and, more particularly, but not exclusively, to dipeptides and analogs thereof, which prevent amyloid fibril formation and thus can be used in the treatment of amyloid associated diseases, such as type II diabetes mellitus, Alzheimer's dementia or diseases, systemic and localized amyloidosis, ocular diseases or disorders (e.g., glaucoma) and prion-related encephalopathies.
Amyloid material deposition (also referred to as amyloid plaque formation) is a central feature of a variety of unrelated pathological conditions including Alzheimer's disease, prion-related encephalopathies, type II diabetes mellitus, familial amyloidosis and light-chain amyloidosis.
Amyloid material is composed of a dense network of rigid, nonbranching proteinaceous fibrils of indefinite length that are about 80 to 100 Å in diameter. Amyloid fibrils contain a core structure of polypeptide chains arranged in antiparallel or parallel β-pleated sheets lying with their long axes perpendicular to the long axis of the fibril [Both et al. (1997) Nature 385:787-93; Glenner (1980) N. Eng. J. Med. 302:1283-92; Balbach et al. (2002) Biophys J. 83:1205-16].
Approximately twenty amyloid fibril proteins have been identified in-vivo and correlated with specific diseases. These proteins share little or no amino acid sequence homology, however the core structure of the amyloid fibrils is essentially the same. This common core structure of amyloid fibrils and the presence of common substances in amyloid deposits suggest that data characterizing a particular form of amyloid material may also be relevant to other forms of amyloid material and thus can be implemented in template design for the development of drugs against amyloid-associated diseases such as type II diabetes mellitus, Alzheimer's dementia or diseases, ocular diseases and disorders and prion-related encephalopathies.
Furthermore, amyloid deposits do not appear to be inert in vivo, but rather are in a dynamic state of turnover and can even regress if the formation of fibrils is halted [Gillmore et al. (1997) Br. J. Haematol. 99:245-56].
Thus, therapies designed to inhibiting the production of amyloid polypeptides or inhibiting amyloidosis may be useful for treating amyloid associated diseases.
One of the currently investigated therapeutic approaches of preventing amyloid fibril formation involves small molecules which can enter the CNS and disrupt polymerization of amyloid-beta peptides. Exemplary such compounds that have been reported in the art as effective in animal models include cyclohexanehexyl [McLaurin et al., Nature Medicine 12(7), 2006, pp. 801-808], including AZD-103; curcumin (Yang et al., J. Biol. Chem., 208(7), 2005, 5892-5901; and hydroxycholesterol derivatives, described and claims in WO 03/077869.
Some of the present inventors have previously disclosed that peptide aggregation into amyloid fibrils is governed by aromatic interactions. Based on these findings, a series of short peptides comprising an aromatic amino acids and a beta-sheet breaker amino acid was prepared and found effective in inhibiting amyloid fibril formation. U.S. Pat. No. 7,781,396 describes and claims such dipeptides. A potential peptide disclosed therein is the dipeptide D-Trp-Aib. Derivatives of this dipeptide are also disclosed therein.
Additional background art includes U.S. Pat. No. 7,732,479, and Yescovi et al. [Org. Biomol. Chem., 2003, 1, 2983-2997].